Webber A L, Ingram R S, Levorse J M, Tilghman S M
Howard Hughes Medical Institute and Department of Molecular Biology, Princeton University, New Jersey 08544, USA.
Nature. 1998 Feb 12;391(6668):711-5. doi: 10.1038/35655.
Genomic imprinting is the process in mammals by which gamete-specific epigenetic modifications establish the differential expression of the two alleles of a gene. The tightly linked H19 and Igf2 genes are expressed in tissues of endodermal and mesodermal origin, with H19 expressed from the maternal chromosome and Igf2 expressed from the paternal chromosome. A model has been proposed to explain the reciprocal imprinting of these genes; in this model, expression of the genes is governed by competition between their promoters for a common set of enhancers. An extra set of enhancers might be predicted to relieve the competition, thereby eliminating imprinting. Here we tested this prediction by generating mice with a duplication of the endoderm-specific enhancers. The normally silent Igf2 gene on the maternal chromosome was expressed in liver, consistent with relief from competition. We then generated a maternal chromosome containing a single set of enhancers located equidistant from 1gf2 and H19; the direction of the imprint was reversed. Thus, the location of the enhancers determines the outcome of competition in liver, and the strength of the H19 promoter is not sufficient to silence Igf2.
基因组印记是哺乳动物中的一种过程，通过该过程，配子特异性表观遗传修饰建立了一个基因两个等位基因的差异表达。紧密连锁的H19和Igf2基因在内胚层和中胚层来源的组织中表达，H19从母本染色体表达，Igf2从父本染色体表达。已提出一个模型来解释这些基因的相互印记；在该模型中，基因的表达受其启动子之间对一组共同增强子的竞争支配。可能预计额外的一组增强子会缓解这种竞争，从而消除印记。在这里，我们通过生成具有内胚层特异性增强子重复的小鼠来测试这一预测。母本染色体上通常沉默的Igf2基因在肝脏中表达，这与竞争缓解一致。然后我们生成了一条母本染色体，其包含一组位于距1gf2和H19等距离位置的增强子；印记方向发生了逆转。因此，增强子的位置决定了肝脏中竞争的结果，并且H19启动子的强度不足以使Igf2沉默。
